Changes in the Ionic Basis of GABAergic Inhibition that Contribute to Post-traumatic Epilepsy

导致创伤后癫痫的 GABA 能抑制离子基础的变化

• 批准号: 10713240
• 负责人: Kevin J. Staley
• 金额: $ 137.95万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713240
• 关键词: Acute; Animals; Anticonvulsants; Antiepileptogenic; Area; Automobile Driving; Behavior; Brain; Brain Injuries; Chloride Ion; Chlorides; Chondroitinases; Chronic; Cicatrix; Compensation; Data; Disinhibition; Electroencephalography; Elements; Epilepsy; Epileptogenesis; Etiology; Extracellular Matrix; Extracellular Space; Family suidae; Functional disorder; Funding; Gliosis; Goals; Human; Image; Injury; Intractable Epilepsy; Investigation; Kinetics; Matrix Metalloproteinase Inhibitor; Measures; Mediating; Medical; Membrane; Microscope; Microscopy; Miniature Swine; Modeling; Neocortex; Neurons; Phase; Photons; Post-Traumatic Epilepsy; Proteoglycan; Research; Research Personnel; Research Support; Resected; Resolution; Seizures; Signal Transduction; Structure; Sulfate; System; Testing; Time; Translational trial; Trauma; animal facility; brain remodeling; brain tissue; cost; driving force; experimental study; extracellular; fluorescence lifetime imaging; gamma-Aminobutyric Acid; high throughput screening; imaging facilities; in vitro Model; in vivo; in vivo calcium imaging; injured; multiphoton imaging; neocortical; novel; pharmacologic; preservation; prevent; programs; prophylactic; receptor; reconstruction; screening program; tool; two-photon

Brain injury is a common cause of medically intractable epilepsy. Because we do not understand the underlying pathophysiology, we can’t reduce the burden of medical intractability. The overarching goal of this research program is to exploit a recently developed large animal gyrencephalic model of neocortical post-traumatic epilepsy (PTE) to elucidate a mechanism of neocortical epileptogenesis: chronic compromise of the ionic basis for GABA-mediated inhibition. Disinhibition is a fundamental element of ictogenesis, but thus far we have not found the mechanism of disinhibition in chronic epilepsy. There are two salient clues: first, anticonvulsants that increase GABA conductance often do not ameliorate PTE; and second, studies in human intractable epilepsy have found a positive, disinhibitory shift in the reversal potential for GABAA receptor-mediated membrane currents (EGABA). Here we will test the hypothesis that glial reconstruction of the brain’s extracellular matrix after injury results in increased displacement of extracellular chloride (Cl-o) by the sulfate moieties of the proteoglycans that comprise the new matrix. To test this hypothesis, we will employ a large-animal PTE model in which local epileptogenesis occurs after well-characterized neocortical injury (Project 1 and Large Animal Core). This localization of epileptogenesis is critical for correlation of changes in Cl-o, network structure, and epilepsy. In this injured neocortical area, we will use longitudinal 2-photon in vivo calcium imaging to test for the network changes expected from disinhibition (Project 2 and Microscopy Core). In the injured neocortical area, we will use 2-photon Fluorescence Lifetime Imaging (FLIM) and newly-synthesized Cl- indicators to test for changes in the local Cl-o and intracellular chloride (Cl-i ) that would drive disinhibition by depolarizing EGABA and reducing the efficacy of shunting inhibition (Project 3). The 3 projects have a common third aim: to correlate epileptogenesis (Project 1) with network disinhibition (Project 2) that are associated with chronic changes in Cl-o and Cl-i (Project 3). Together, these Projects and Cores will test a novel mechanism of epileptogenesis and medical intractability that could be ameliorated by short-term inhibition of the disassembly of the brain’s extracellular matrix at the time of injury using MMP inhibitors whose efficacy will be screened in Project 3, Aim 2.

脑损伤是医学上难治性癫痫的常见原因。因为我们不懂